‘It is a flaw in our cells that becomes a flaw in love’: doctor Siddhartha Mukherjee on the search for a cure for depression

I was overwhelmed by a wave of depression in the spring of last year. When it finally burst on me, having crept up slowly for months, I felt as if I was drowned in a tide of sadness. I felt drenched in grief even though my life seemed perfect. It was hard to get out of bed or get the newspaper out of the door. Simple moments of pleasure, such as my child's drawing of a weeping shark, seemed locked away in boxes, with all their keys thrown into the ocean.

What's the reason? I didn't know. It may have been coming to terms with my father's death a year prior. I neglected to give myself time and space to grieve after he died. It was facing the inevitability of old age. I was at a point in my life where I felt like I was in a bad place. I hurt my knees running. There was a hernia out of the blue. Is it possible to recite the poems from memory? I would have to look in my brain for words that had disappeared. I was getting lost. My brain was the one that had begun to droop. I heard a loud noise.

Things didn't get better. I didn't deal with it until it had crested. The frog in the pot didn't sense the rise in temperature until the water started boiling. I started seeing a Psychiatrist and began to see more results. I was perplexed by the sudden wave of the disorder. I didn't know what I was missing. The writer William Styron described joylessness in his book.

I drew parallels between the history of cell biology that I was researching and the joylessness of my life when I wrote The Song of the Cell. The physician-scientist had said that all pathology is cellular pathology. We had to understand the function and function of cells in order to understand the core of an illness.

I focus on cells that have gone rogue. To understand my mental anguish, I needed to understand a cellular anguish

I am an oncologist and cell biologist and that insight fromVirchow was very touching to me. You might think of me as a cell biologist caught in an upside-down world, because the normal biology of cells in my lab are distorted by cancer cells. It was only natural that I would try to understand the core of my depression in terms of my brain abnormality, because the story of the cell is woven into my scientific life. I need to understand my cellular anguish first to understand my mental anguish.

Paul Greengard is a professor at Rockefeller University. I had met Greengard at a retreat in Maine several years earlier, we had recognised each other as fellow scientists, and we walked for a mile on a white-pebbled, windswept beach, talking about cells and biochemistry. When we met, he was considerably older than me, but his mind was still youthful. Many of our conversations were wide open. Greengard was interested in Neuroscience, cell biology, university gossip, politics, friends, the latest exhibition at the Museum of Modern Art, the newest findings in cancer research.

Greengard invited me to lunch when I told him about the grief I was feeling. We ate at the university cafeteria and he was a slow, fastidious eater, looking at each piece of food on his fork as if it were a biological specimen before putting it in his mouth. Alpha was by our side.

He said that depression is a brain problem. Slow is important here. Greengard was able to come up with a new way of thinking about communication. Neuroscience used to describe the communication between neurons as a rapid process. An electrical impulse at the end of a neuron causes the release of a neurotransmitter into a special space between two cells. The chemical channels open in the next part of the brain. This is the electrical brain, a box of wires and circuits, and it usually happens in about a minute.

Greengard found that some forms of neuroscience involved a deliberative process. Slow signals in the neuron are created by the chemical signals sent out by one neuron. Changes in the recipient cell are caused by neuronal signalling from one cell to another. It might take days for these changes to be established in the brain's complex circuits. The slow cascade was considered peripheral for a long time. The greengard cascade is a type of biochemical alterations produced in neuronal cells. The 2000 prize in medicine was won by Greengard.

Over the next two decades, Greengard accumulated evidence that these changes were the root of many mental illnesses. Carl Sandburg wrote a poem about the fog coming on little cat feet and then moving on. As if some creature had descended on silent haunches, my brain was fogged.

Andrew Solomon once described depression as a curse in love. Greengard may suggest that it was a flaw in the cells. There is a flaw in the signals they cause. There is a flaw that alters the composition, metabolism, signalling and behaviour of neurons that regulate mood.

Which chemical? What does it mean? I wanted to know.

Serotonin, the neurotransmitter, was involved. Greengard told me the story of how the brain chemical theory came about. In the autumn of 1951, doctors treating tubercular patients at Sea View hospital on Staten Island with a new drug had observed sudden changes in their patients' moods and behaviors. The wards were cheerful last week with the happy faces of men and women. The appetites came back and the energy came back. Patients who were ill and catatonic for a long time wanted five eggs for breakfast. Patients were no longer lying in their beds when Life magazine sent a photographer to the hospital. They were moving quickly in the corridors.

The researchers found that the drug increased the levels of a brain chemical. Psychiatry was gripped by the idea that depression was caused by the lack of the neurotransmitters. The electrical circuits that respond to the chemical don't get enough stimulation because there isn't enough Serotonin in the sphinx. Depression is caused by insufficient stimulation of mood-regulating cells.

Serotonin should be increased in the brain if there was only one cause of depression. This theory is called the "loud speaker hypothesis" of depression. The mood-regulating cells in the brain have begun to mumble inaudibly. The pathological mumble that leads to joylessness and grief will be restored if the volume of the chatter is increased.

In the 70s, Arvid Carlsson, a researcher at the University of Gothenburg in Sweden, collaborated with a Swedish pharmaceutical company to develop a drug that increased the levels of the neurotransmitter in the brain. Prozac and Paxil are examples of drugs that increase the levels of a brain chemical called Serotonin. Some depressed patients, who were treated with theseSSRIs, had profound remissions in their disease. The author of Prozac Nation wrote of a transformational experience in her book. She was floating from one suicidal reverie to the next before she started treatment. Her life changed a few weeks after she started Prozac. It was as if the miasma of depression had lifted off me, in the same way that the fog in San Francisco rises as the day goes on.

The response to SSRIs was mixed. In some trials with the most depressed patients, there was a measurable improvement in symptoms for those who received the drug compared to those who did not, but in other trials the effect was marginal. The time it took to get the effect, often weeks or months, did not suggest that raising the level of Serotonin could cure depression. The fog in my brain didn't lift when I took Paxil and Prozac. It was obvious that adjusting the level of the drug in the brain couldn't be the solution.

A woman was about to have holes bored into her head and she felt nothing. That’s when I knew how bad it was for her

Greengard agreed. His lab at Rockefeller University had found a pathway that might be responsible for depression. Serotonin, Greengard and other researchers found that depression isn't just a malfunctioning neuronal circuit that can be reset by increasing Serotonin in the strontium. Serotonin sets off a slow signal in the brain, which is a signal that comes from cat's feet. Greengard believed that the slow signalling in the brain is important to emotional and mood regulation.

Greengard said that it wasn't just the level of Serotonin. The New York air was clear and cold, and he had a mist behind him. It is way too easy. Serotonin is what it does to the brain. He said that the way it changed the chemistry of the neuron. It might be different from one person to the next. He looked at me. The response may be more difficult to sustain or restore due to inputs or genetic reasons.

Greengard said they were looking for new drugs that would affect the pathway. He was trying to find a new way to treat depression.

The walk had ended. He didn't touch me, but I felt like he had healed something inside of me. He came back to his lab. Greengard was excited and Alpha was tired.

Love is affected by depression. It is a flaw in how the brain responds to neurotransmitters. Greengard believed that it was more than just a wiring problem, it was a cellular disorder that was caused by a signal that was instigated by neurotransmitters. A flaw in our cells leads to a flaw in love.

Greengard died of a heart attack at the age of 93. I am missing him a lot.

I met Helen Mayberg at Mount Sinai hospital. I was stung by the wind on my way to her office. The leaves were getting ready for the winter. Advanced CircuitTherapeutics is a centre run by Mayberg, who is a neurologist. She is one of the pioneers of a technique called deep brain stimulation. Tiny bolts of electricity are sent to the cells of the brain that are malfunctioning. Mayberg wants to treat the most resistant forms of depression with electrical stimulation of the brain. It is a therapy for the cells.

Mayberg began to use a variety of techniques to map cellular circuits in the brain that may be responsible for depression in the early 2000s. Researchers noted that deep brain stimulation could improve coordination of movement in Parkinson's patients. It wasn't yet possible to try DBS in depression. Mayberg found one area of the brain, called the Brodmann area 25 (BA25), which seems to regulate emotional tone, anxiety, motivation, drive, and self- reflection. Patients with depression were found to have a high level of BA25 in them. She knew that chronic electrical stimulation could affect the activity of the brain. Mayberg believed that electrical stimulation could relieve the symptoms of depression.

Brodmann area 25 is hard to get to. The middle finger of the human brain can be seen in the deep center of the clutch, just where the brain folds into a boxing glove. One journalist described it as a pair of pale- pink curves of neural flesh called the subcallosal cingulate, each about the size and shape of a newborn's crooked finger. In 2003 Mayberg collaborated with neurosurgeons in Toronto to conduct a trial to implant electrodes on both sides of the brain in patients with treatment-resistant depression. It was not easy to make a newborn laugh.

The patients ranged in age from 37 to 48 years old. I asked Mayberg if he remembered each patient. The first person was a nurse. She described herself as completely numb. She used metaphors for her illness that were vertical. There was a hole. She fell into it. Some people would talk about caves and force fields. It was important to listen to the metaphors. The metaphors allowed me to know if a patient was responding or not.

The frame that was put around the patient's head was similar to a three-dimensional gps system to track the electrode's position as the surgeon introduced it into the brain. The patient looked at her without fear as Mayberg tightened the clasps. She was about to have holes bored into her head and a completely new procedure done in her brain, and all she could think about was numbness. There's nothing. I knew how bad it was for her when I saw that.

Mayberg took her to the hospital. We were so worried. We didn't know what the stimulation would do. Is it possible that it would cause the blood pressure to go down? Are neuroscientists aware of a cellular circuit that they didn't know about? Is it possible to unleash some unexpected psychotic tendencies? The surgeon bored through the patient's skull and inserted a pair of wires. Mayberg turned on the current and gradually increased the frequencies.

Mayberg said that it occurred. The patient suddenly asked "what did you do?" as we hit the right spot.

Do you mean what you say? Mayberg wanted to know.

You did something and the void lifted.

There was a void. The stimulator was turned off.

Maybe I felt strange. Don't worry.

Mayberg put it on again. There was a void again. Mayberg asked her to describe the thing.

I don't know if I can. It is like the difference between smiling and laughing.

Mayberg said that you have to listen to the metaphors. There is a difference between smiling and laughing. There was a picture in her office of a stream with a large hole in the middle. The picture was sent to me by a patient. There is another hole. The traps are vertical. The woman said that when Mayberg turned on the stimulator, she lifted herself out of the sinkhole and sat on a rock above the water. She could see herself in the hole, but she was on a rock. These pictures and descriptions tell you a lot more.

Deep brain stimulation has gone through its own cyclical mood disorder: hopelessness, optimism, despair, cautious hope

Mayberg has treated many people with deep brain stimulation. She told me that they don't know why everyone doesn't reply. The effect is almost instantaneous in some patients. A nurse described her illness as a complete incapacity to feel emotional or sensory connections. She said that when she held her own children, she didn't feel anything. There was no sensation, no comfort, and no pleasure. The patient turned to Mayberg and asked what was strange. I feel like I'm in touch with you. A patient remembered the exact moment of her illness. She felt that all the colors had gone as she walked her dog. Black and white were what they had become. It could be grey. The patient looked frightened when Mayberg turned on the device. The colors came out. Another woman said her response was like a season was about to start. She felt the portent of spring even though it wasn't spring yet. There is a flower called the crocuses. The people just came out.

Mayberg didn't understand all the mysteries. Depression has a psychomotor component to it. They are catatonic after lying in bed. When the DBS is turned on, patients want to move again, but they also want to clean out rooms. The garbage is being taken out of the kitchen. There are dishes that need to be washed. The patient used to be a thrill-seeker. He would leap out of the plane. He said he wanted to go back to his old home.

What would you like to do? Mayberg inquired about him.

I would like to clean my garage.

There are stringent studies that are focused on the treatment of treatment- resistant depression. The study was halted because early data did not show the kind of efficacy that Mayberg had seen in her previous studies. When data was available on about 90 patients who had had the surgery for at least six months, their depression scores were not better than those of the control group. Patients with the implant had a lot of problems after the surgery. Some had anxiety, some had intolerable headaches, and some had increased depression and infections.

There are a number of reasons why the Broaden study went wrong, according to Mayberg. We need to find the right patient, the right area and the right way to watch the response. There are a lot of things we have to learn. Her critics are still unconvinced. Drugs are out andceuticals are in.

The patients in the halted study who kept their devices on began to experience powerful and objective responses. I was reminded of Greengard's cascade again, maybe it takes weeks before the brain chemistry that regulates cellular mood can "reset" itself. The fundamental behavior and nature of the cell can be changed by the levels of neurotransmitters. The process of permanently altering a mood-regulating circuit may take months.

When patients were tracked for two years instead of the six months used in the initial analysis, 31% had experienced a remission, close to the rate that Mayberg had documented in her initial studies. There's renewed enthusiasm for the treatment of depression. The study needs to be done the right way, according to Mayberg. The field has gone through a series of moods: hopelessness, followed by ecstatic optimism, and finally a return to despair. There is renewed hope after a long time. It seemed to me that November had started to feel like a turning point in the season. I knew that the gardens outside Mount Sinai West would bloom in February even though there were no crocuses there.

Deep brain stimulation, also known as cell circuit therapy, is being tried for a variety of neurological disorders, including obsessivecompulsive disorder and addiction.

The electrical stimulation of cellular circuits is trying to become a new type of medicine. Some of these attempts might work. If these attempts are successful, they will create a new kind of person, one that is implanted with brain pacemakers. They will go through airport security and say that they have a battery in their body that sends impulses into their brain to regulate their moods.

Maybe I'll be one of them.